Cellular therapy is an emerging field of medicine that uses cells that evolve from transplanted progenitor cells or genetically-modified cells to repair damaged tissue and diseased organs, or to generate new tissues with desired functions. Stem cell therapy presents a way to treat many degenerative diseases caused by death or malfunction of specific body tissues by replacing or restoring the damaged tissue cells.
Cellular therapy is currently used to treat leukemia by transplanting bone marrow that contains blood progenitor cells or genetically-modified cells which differentiate into new, cancer-free blood cells. Body organs that may potentially be treated using progenitor or genetically-modified cell therapy include body muscles and bones, nerves, skin, blood cells, the heart, the brain, the liver, the pancreas, and the spinal cord. Conditions that may be treated using such cell therapy include leukemia, sickle cell anemia, spinal cord injury, heart disease, Parkinson's disease, Alzheimer's disease, burns, cirrhosis, hepatitis, muscular dystrophy, diabetes, arthritis, and osteoporosis-related injuries.
Bone marrow progenitor or genetically-modified cell therapy for cardiac repair has been tested in animal models and has shown some evidence of increased neovascularization (with reduced myocardial ischemia) and consequent improvement in cardiac function (Tang Y L et al., Duan H F et al., and Kudo M et al., cited hereinbelow). It has also been shown that bone marrow progenitor cells or genetically-modified cells may directly contribute to an increase in contractility, and may limit infarct expansion and remodeling. One of the obstacles for successful engraftment of the stem cells is insufficient blood supply and angiogenesis. The use of growth factors to promote arteriogenesis and vasculogenesis, which may result in cardiac repair, has been evaluated (e.g., see the two articles cited hereinbelow by Kinnaird T et al.).
The use of nerve stimulation for treating and controlling a variety of medical, psychiatric, and neurological disorders has seen significant growth over the last several decades, including for treatment of heart conditions. In particular, stimulation of the vagus nerve (the tenth cranial nerve, and part of the parasympathetic nervous system) has been the subject of considerable research. The vagus nerve is composed of somatic and visceral afferents (inward conducting nerve fibers, which convey impulses toward the brain) and efferents (outward conducting nerve fibers, which convey impulses to an effector to regulate activity such as muscle contraction or glandular secretion).
US Patent Application Publication 2004/0158290 to Girouard et al., which is incorporated herein by reference, describes a method for cell and electrical therapy of living tissue including administration of exogenous cells into a region of injured tissue and application of electrical energy. In one application, the combined cell and electrical therapy is applied in vivo to damaged heart tissue. Minimally-invasive procedures are used to apply the cell therapy, and the electrical therapy is provided via an implantable pulse generator. In one application, an implantable pacemaker is used in the VDD mode with an atrioventricular delay kept relatively short when compared to the intrinsic atrioventricular delay.
US Patent Application Publication 2005/0288721 to Girouard et al., which is incorporated herein by reference, describes a system that delivers cardiac pacing therapy and chemical and/or biological therapy to modulate myocardial tissue growth in a heart after myocardial infarction (MI). The system includes an agent delivery device to release one or more agents to an MI region to modulate myocardial tissue growth in that region, and a cardiac rhythm management (CRM) device to deliver pacing pulses to enhance the effects of the one or more agents by altering myocardial wall stress and cardiac workload. In an embodiment, the agent includes a vector, which may include a coding sequence of interest for gene therapy. For some applications, the agent enhances localization, implantation, or proliferation of stem cells at the cardiac region. For some applications, cellular engraftment, cellular proliferation, cellular differentiation, cellular survival, and/or cellular function, e.g., contractile function, of the donor cells in the recipient is further enhanced by the electrical therapy and/or agent administration.
US Patent Application Publication 2005/0192637 to Girouard et al., which is incorporated herein by reference, describes a gene regulatory system that controls gene therapy by emitting one or more forms of energy that regulate gene expression by triggering promoters. The system includes a sensor to sense a signal indicative of a need for the gene therapy as well as responses to the gene therapy. The regulation of the gene expression is controlled based on the sensed signal and/or a user command. In an embodiment, the system delivers one or more electrical therapies in conjunction with the gene therapy.
US Patent Application Publication 2006/0015146 to Girouard et al., which is incorporated herein by reference, describes an implantable system which includes a gene/protein delivery device and a pulse generator, as well as a method for preparing the gene/protein delivery device and using the system. In an embodiment, the implantable system detects a predetermined condition or event and, in response, delivers gene(s) and/or protein(s) in conjunction with delivering pacing and/or defibrillation pulses.
U.S. Pat. No. 6,348,444 to Chappel, which is incorporated herein by reference, describes techniques for the use of human growth hormone for the manufacture of a medicament for stimulating hematopoiesis and immune reconstitution to be administered to a patient in need thereof about 30 days post-transplantation of hematopoietic stem cells.
US Patent Application Publication 2004/0247574 to Christopherson et al., which is incorporated herein by reference, describes techniques for improving engraftment efficiency in stem cell transplants by improving stem cell homing to bone marrow.
U.S. Pat. No. 6,383,481 to Ikehara et al., which is incorporated herein by reference, describes techniques for transplanting hemopoietic stem cells, which comprise subjecting a recipient to a radiation treatment using an effective exposure dose for hemopoietic stem cell transplantation in advance and administering hemopoietic stem cells from a donor from the portal vein.
US Patent Application Publication 2002/0182186 to Loeb, which is incorporated herein by reference, describes techniques for use with stem cells, bone marrow, or bone marrow enriched with stem cell compositions suitable for tissue repair.
The following articles, all of which are incorporated herein by reference, may be of interest:
Perin E C et al., “Stem cell therapy for cardiac diseases,” Curr Opin Hematol 11(6):399-403 (2004)
Tang Y L et al., “Autologous mesenchymal stem cell transplantation induce [sic] VEGF and neovascularization in ischemic myocardium,” Regul Pept 117:3-10 (2004)
Duan H F et al., “Treatment of myocardial ischemia with bone marrow-derived mesenchymal progenitor cells or genetically-modified cells overexpressing hepatocyte growth factor,” Mol Ther 3:467-474 (2003)
Kudo M et al., “Implantation of bone marrow progenitor cells or genetically-modified cells reduces the infarction and fibrosis in ischemic mouse heart,” J Mol Cell Cardiol 35:1113-1119 (2003)
Kinnaird T et al., “Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms,” Circulation 109:1543-1549 (2004)
Kinnaird T et al., “Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms,” Circ Res 94:678-685 (2004)
Borovikova L V et al., “Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin,” Nature 405(6785):458-62 (2000)
Wang H et al., “Nicotinic acetylcholine receptor alpha-7 subunit is an essential regulator of inflammation,” Nature 421:384-388 (2003)
Vanoli E et al., “Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction,” Circ Res 68(5):1471-81 (1991)
De Ferrari G M, “Vagal reflexes and survival during acute myocardial ischemia in conscious dogs with healed myocardial infarction,” Am J Physiol 261(1 Pt 2):H63-9 (1991)
Li D et al., “Promotion of Atrial Fibrillation by Heart Failure in Dogs: Atrial Remodeling of a Different Sort,” Circulation 100(1):87-95 (1999)
Feliciano L et al., “Vagal nerve stimulation during muscarinic and beta-adrenergic blockade causes significant coronary artery dilation,” Cardiovasc Res 40(1):45-55 (1998)
Tracey K J, “The inflammatory reflex,” Nature Vol 420 19/26 December 2002
Bernik T R, “Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway,” J. Exp. Med. Volume 195, Number 6, Mar. 18, 2002 781-788
Blalock J E, “Harnessing a Neural-immune Circuit to Control Inflammation and Shock,” J. Exp. Med. Volume 195, Number 6, Mar. 18, 2002 F25-F28
US Patent Publication 2003/0045909 to Gross et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for treating a heart condition of a subject, including an electrode device, which is adapted to be coupled to a vagus nerve of the subject. A control unit is adapted to drive the electrode device to apply to the vagus nerve a stimulating current, which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve. The control unit is also adapted to drive the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
PCT Publication WO 02/085448 to Foreman et al., which is incorporated herein by reference, describes a method for protecting cardiac function and reducing the impact of ischemia on the heart, by electrically stimulating a neural structure capable of carrying the predetermined electrical signal from the neural structure to the “intrinsic cardiac nervous system,” which is defined and described therein.
U.S. Pat. No. 6,610,713 to Tracey, which is incorporated herein by reference, describes apparatus for inhibiting inflammatory cytokine production, for treating a condition mediated by the cytokine cascade such as allergy, asthma, sepsis, septic abortion or urethritis. The apparatus uses cholinergic agonist and vagus nerve stimulation.
US Patent Publication 2003/0050677 to Gross et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for applying current to a nerve. A cathode is adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve and to apply a cathodic current to the nerve. A primary inhibiting anode is adapted to be placed in a vicinity of a primary anodal longitudinal site of the nerve and to apply a primary anodal current to the nerve. A secondary inhibiting anode is adapted to be placed in a vicinity of a secondary anodal longitudinal site of the nerve and to apply a secondary anodal current to the nerve, the secondary anodal longitudinal site being closer to the primary anodal longitudinal site than to the cathodic longitudinal site.